PPARs are known to be a family of nuclear receptors, and three sub-types thereof (α, γ, δ) have already been identified (Non-Patent Documents 1 to 5). Among the three sub-types, PPARα is expressed mainly in the liver and is known to be activated by a plasticizer or a fibrate-type drug such as Wy 14643 or a commercially available pharmaceutical; e.g., clofibrate, fenofibrate, bezafibrate, or gemfibrozil (Non-Patent Documents 6 and 7).
In mammals, activation of PPARα is known to promote β oxidation of fatty acids and to lower blood triglyceride level, and in humans, blood lipid levels such as low-density lipoprotein (LDL) cholesterol level and very low-density lipoprotein (VLDL) cholesterol level are known to decrease. Thus, a PPARα-activating agent is considered a useful drug for preventing and/or treating diseases such as hyperlipidemia. In addition, the PPARα-activating agent, which increases high-density lipoprotein (HDL) cholesterol level and, in blood vessels, suppresses expression of VCAM-1 (a type of cell adhesion factor), is considered to be useful for preventing and/or treating diseases such as arteriosclerosis, and for preventing and/or treating diseases such as diabetes, inflammatory disease, and heart diseases (Non-Patent Documents 8 to 14).
Activation of PPARγ in humans has been reported to cause adverse effects of increasing the amount of fat and body weight and causing obesity (Non-Patent Document 15). Recent studies have reported that a PPARγ antagonist also possibly improves insulin resistance (Non-Patent Documents 16 to 18). A document reports that activation of PPARδ causes lipid accumulation (Non-Patent Document 19). Therefore, a PPARα-selective activator having low activation property with respect to PPARγ and to PPARδ is promised to be useful for prevention and/or treatment, without accompanying obesity or increase in body weight, of pathological conditions including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.
Under such circumstances, the present inventors previously found that compounds represented by formula (A):
[F1]
(wherein R1 and R2, which may be identical to or different from each other, each represent a hydrogen atom, a methyl group, or an ethyl group; R3a, R3b, R4a, and R4b, which may be identical to or different from one another, each represent a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a C1-4 alkoxy group, a C1-4 alkylcarbonyloxy group, a di-C1-4 alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4 alkylsulfonyl group, a C1-4 alkylsulfinyl group, or a C1-4 alkylthio group; linkage of R3a and R3b, or linkage of R4a and R4b forms an alkylenedioxy group; X represents an oxygen atom, a sulfur atom, or N—R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkylsulfonyl group, or a C1-4 alkyloxycarbonyl group); Y represents an oxygen group, an S(O)1 group (wherein 1 is an integer of 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group; Z represents CH or N; n is an integer of 1 to 6; and m is an integer of 2 to 6) and salts thereof selectively activate PPARα, and therefore being useful as a drug, and filed a patent application (Patent Document 1).    Patent Document 1: WO 05/023777 pamphlet    Non-Patent Document 1: Nature, 347, 645-650, 1990    Non-Patent Document 2: Cell, 68, pp. 879-887, 1992    Non-Patent Document 3: Cell, 97, pp. 161-163, 1999    Non-Patent Document 4: Biochim. Biophys. Acta., 1302, pp. 93-109, 1996    Non-Patent Document 5: Journal of Medicinal Chemistry, 43, pp. 527-550, 2000    Non-Patent Document 6: Journal of the National Cancer Institute, 90, 1702-1709, 1998    Non-Patent Document 7: Current Opinion in Lipidology, 10, pp. 245-257, 1999    Non-Patent Document 8: Journal of Atherosclerosis and Thrombosis, 3, pp. 81-89, 1996    Non-Patent Document 9: Current Pharmaceutical Design, 3, pp. 1-14, 1997    Non-Patent Document 10: Current Opinion in Lipidology, 10, pp. 151-159, 1999    Non-Patent Document 11: Current Opinion in Lipidology, 10, pp. 245-257, 1999    Non-Patent Document 12: The Lancet, 354, pp. 141-148, 1999    Non-Patent Document 13: Journal of Medicinal Chemistry, 43, pp. 527-550, 2000    Non-Patent Document 14: Journal of Cardiovascular Risk, 8, pp. 195-201, 2001
Non-Patent Document 15: The Lancet, 349, pp. 952, 1997    Non-Patent Document 16: Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999    Non-Patent Document 17: The Journal of Biological Chemistry, 275, pp. 1873-1877, 2000    Non-Patent Document 18: J. Clin. Invest., 108, 1001-1013, 2001    Non-Patent Document 19: Proc. Natl. Acad. Sci., 99, pp. 303-308, 2002